Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes

Article abstract of DOI:10.1016/j.bmcl.2020.127681

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D₂/D₃/5-HT_1A/5-HT_2A receptors and weak α₁ and H₁ receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

Full text of DOI:10.1016/j.bmcl.2020.127681

Journal Pre-proofs
Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-
tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives tar‐
geting dopamine/serotonin receptor subtypes
Jun-Wei Xu, Yang-Li Qi, Jian-Wei Wu, Rui-Xiang Yuan, Xiao-Wen Chen,
Jian-Qi Li
PII:
S0960-894X(20)30792-7
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127681
BMCL 127681
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Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
25 August 2020
2 November 2020
6 November 2020
Please cite this article as: Xu, J-W., Qi, Y-L., Wu, J-W., Yuan, R-X., Chen, X-W., Li, J-Q., Synthesis and
biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-
yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes, Bioorganic &
Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127681
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Synthesis
and
biological
evaluation
of
novel
antipsychotic
trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine
derivatives targeting dopamine/serotonin receptor subtypes
Jun-Wei Xu1, Yang-Li Qi1, Jian-Wei Wu, Rui-Xiang Yuan, Xiao-Wen Chen*, Jian-Qi Li*
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road,
Shanghai 201203, P.R. China
*Corresponding author: Tel.: +86-021-20572000. E-mail: cxwvio423@163.com;
lijianqb@126.com
1These authors contributed equally to this work.
Abstract
In
this
study,
a
series
of
trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine
derivatives as potential antipsychotics were synthesized and biologically evaluated to
discover potential antipsychotics with good drug target selectivity. The preliminary
structure-activity relationship was discussed, and optimal compound 12a showed both
nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor
binding affinity. In addition, 12a was metabolically stable in vitro, displayed
micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the
animal model of locomotor-stimulating effects of phencyclidine.
Keywords
Antipsychotic; DA receptor; 5-HT receptor; α1 receptor; H1 receptor
1

Schizophrenia is one of the most complex and
debilitating mental disorders
characterized by positive, negative, and cognitive symptoms.1 About 0.5-1.0% of the
population worldwide is diagnosed with this condition,2 about 20% of which has
chronic symptoms and disability, and more than 50% has intermittent but long-term
psychiatric problems.3 The unemployment rate in individuals with schizophrenia is
very high at 80-90%,4 and life expectancy is reduced by 10-20 years.5
Since the 1950s approval of chlorpromazine, several typical antipsychotics
(TAs) and atypical antipsychotics (ATs) have been developed. TAs, referred to as
dopamine (DA) D2 receptor (D2R) antagonists, are effective in treating positive
symptoms but are ineffective in alleviating negative symptoms or improving cognitive
impairment. TAs can also cause serious side effects such as extrapyramidal symptoms
(EPSs) due to their antagonistic effects on
DA receptors in the nigrostriatal
dopaminergic pathway.6
ATs, ( e.g., lurasidone, risperidone, aripiprazole and
cariprazine, Fig. 1) are characterized by multi-receptor affinity and offer a number
of therapeutic advantages, such as decreasing the incidence of EPSs. However, the
treatment can be impaired by metabolic, cardiovascular and anticholinergic side
effects, which are likely related to binding to other receptors.7,8 These include
weight gain (histamine H1 receptor
[H1R] and serotonin (5-HT)2C receptor
[5-HT2CR] antagonism), orthostatic hypotension (adrenergic α1 receptor [α1R]
antagonism9), and sedation ( H1R antagonism). Therefore, interdisciplinary
collaborations and concerted research efforts are in active progress for the
development of multiple-targets antipsychotics with high efficiency and good drug
target selectivity.
2

Fig. 1. Structures of reference compounds
D2R is effective in treating the positive symptoms1,10 of schizophrenia. D3R
belongs to the subfamily of D2-like receptors and is localized in the limbic system.
D3R antagonists have cognition-enhancing activity which may be of benefit for
the treatment of cognitive dysfunction.11 Moreover, higher binding affinity for D3R
compared with D2R offers regionally selective antidopaminergic activity10,12, resulting
in
heightened effect on positive symptoms along with
a decrease in EPSs.
Antagonists of 5-HT2AR increase the release of DA into the prefrontal cortex,
which is correlated with effects on cognitive and negative symptoms. Partial agonists
of the
recently garnered increasing attention because of its potential to enhance cognition
based on preclinical and clinical evidence.13 A combination of
the therapeutic
5-HT1AR help stabilize the frontal cortex function1. The 5-HT1AR has
effects of these receptors, such as via cariprazine, a D2/D3/5-HT1A partial agonist and
5-HT2A antagonist with 8-fold selectivity for D3R/D2R subtypes, may reduce positive
symptoms14, alleviate negative symptoms, and improve the cognitive impairments15
associated with schizophrenia.
Blockade of the
α1R can result in orthostatic hypotension9, which is an
Clinical first-line
adverse effect caused by many antipsychotic drugs.
antipsychotics all have effects on the H1R, which produces strong to moderate
intensity of sedation and are involved in weight gain. Table 1 displays the affinity of
some market antipsychotics for α1R and H1R.
3

Table 1
Affinity for α1R and H1R of some market antipsychotics.
Ki/nmol·L-1
Drug
α1
H1
20
7
11
50
61
1.0
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Asenapine
0.7
19
7
11
57
1.2
In our previous study on potential multi-target antipsychotics, a series of novel
benzisothiazolylpiperazine cyclohexylamides16 targeting D2/D3/5-HT1A/5-HT2A
receptors were discovered. Among these derivatives, compound I (Fig. 2) showed
unique affinities for the D2/D3/5-HT1A/5-HT2A receptors. Substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepines17,18 reportedly have
5-HTR
subtype
binding affinities without targeting α1R and H1R, as represented by the US Food and
Drug Administration-approved antiobesity agent lorcaserin (compound II, Fig. 2). By
linking this 2,3,4,5-tetrahydro-1H-benzo[d]azepine core with (trans)-ethyl cyclohexyl
linker, a series of potent DA antagonists, such as D3 antagonists were identified, as
represented by compound III (Fig. 2)19. In our continuous effort to develop selective
antipsychotics targeting D2/D3/5-HT1A/5-HT2A receptors based upon these findings,
we
designed
and
evaluated
a
series
of
trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine
derivatives 9, 11a-e, 11a-f, 12a-f and 13a-b (Fig. 2). The target compounds were
evaluated for binding affinity to α1/H1/D2/D3/5-HT1A/5-HT2A receptors . The
preliminary structure-activity relationships (SARs) of target compounds for these
receptors were investigated as the function of various substituents in the amide moiety
and 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl fragment. By systematically varying
the substituents valuated, we identified the trans-tetrahydro-3H-benzo[d]azepin-3-yl
ethyl cyclohexan amine scaffold with weak α1R and H1R binding affinity, and
4

discovered that optimal compound 12a had expected receptor binding profile and
target selectivity. Further pharmacological evaluation was conducted of 12a including
metabolic stability in vitro, hERG channel inhibition and antipsychotic efficacy in
animal behavior models.
Fig. 2 Representative compounds and design of
1,2,4,5-tetrahydro-3H-benzo[d]azepine cyclohexyl amines
The synthesis of all of the intermediates and target compounds was depicted in
Schemes 1-5. Scheme 1
Intermediate 6 was prepared according to our previous method16, which was coupled
with 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine fragments to yield
outlines the synthesis of key intermediates 8a-c.
intermediates 7a-c. Then, 7a-c were refluxed under 3% aqueous hydrochloric acid
conditions to yield the key intermediates 8a-c.
Scheme 1. Reagents and conditions: (i) Triethyl phosphonoacetate, t-BuOK, THF, 0-5°C; (ii) H2,
5%Pd/C, EA, rt; (iii) LiOH·H2O, THF, 10%HCl; EtOH, recrystallization; (iv) EtOH, EDCI,
5

DMAP, rt; (v) NaBH4, MeOH, THF, reflux; (vi) Et3N, MsCl, DMF; (vii) Na2CO3, KI, ACN,
reflux; (viii) 3%HCl, reflux.
Scheme 2 shows the preparation of compounds 9, 10a-d, 12a-e and 13a-b
through acylation. In scheme 3, intermediate 8a along with triethylamine in CH2Cl2
was added to a solution of triphosgene at 0-5°C. Then the substituted amines were
added to the solution yielding 12f-g. Scheme 4 shows the preparation of 11a-e
through the reaction of intermediate 8a with different dicarboxylic anhydrides under
acetic acid conditions. Scheme 5 shows the preparation of compounds 10e and 11f.
Compound 10e was obtained via acylation. Intermediate 8a refluxed with
8-oxaspiro[4.5]decane-7,9-dione (15), generating compound 11f in the presence of
p-toluenesulfonic anhydride.
Scheme 2. Reagents and conditions: (i) R2Cl, TEA, DMAP, CH2Cl2, rt.
Scheme 3. Reagents and conditions: (i) triphosgene, TEA, CH2Cl2, 0-5°C.
6

Scheme 4. Reagents and conditions: (i) DMAP, AcOH, reflux.
Scheme 5. Reagents and conditions: (i) EDCI, DMAP, CH2Cl2; HCl in EA; (ii) TsOH·H2O,
reflux; (iii) Ac2O, NaOAc, reflux.
The target compounds were tested for binding affinities of
α1/H1/D2L/D3/5-HT1A/5-HT2A receptors. The detailed results are summarized in
Table 2. The Ki values were determined when the inhibition ratios were over 90%
measured at a concentration of 10 μM. The following specific radioligands and tissue
sources were used: (a) α1Rs, [3H]prazosin, rat cerebral cortex; (b) H1Rs,
[3H]pyrilamine, human recombinant (HEK-293 cells); (c) D2LRs, [3H]spiperone,
human recombinant (CHO cells); (d) D3Rs, [3H]methyl-spiperone, human
recombinant (CHO cells); (e) 5-HT1ARs, [3H]8-OH-DPAT, human recombinant
(HEK-293 cells); (f) 5-HT2ARs, [3H]ketanserin, human recombinant (HEK-293 cells).
The biological studies were conducted by Eurofins Cerep SA, Celle l'Evescault,
France. The recently launched atypical antipsychotic agent cariprazine was used as a
reference.
7

The metabolic stability of the optimal compound was measured using rat and
human liver microsomes in vitro. The ability to block hERG potassium channels was
determined by electrophysiology using cloned hERG potassium channels expressed in
CHO-K1 cells. The animal behavior model of locomotor-stimulating effects of
phencyclidine was used to evaluate antipsychotic efficacy in vivo.
Table 2
The binding affinities of target compounds for α1/H1/D2L/D3/5-HT1A/5-HT2A
receptors.
Receptor affinity Ki (nM)
Compound
Structure
a
a
b
b
b
a
α1
H1
D2L
D3
5-HT1A 5-HT2A
9
51.3
82.1
93.9
84.0
9.8
101.4
8.1
96.9
81.3%a
191.4
77.3
10a
10b
18.7% 27.0%
57.6% 33.2%
52.7%
56.6%
8.2
10c
10d
35.3% 36.8%
36.4% 32.2%
99.3
20.6
17.5
19.1
69.9%a
98.3
38.2%
69.6%
10e
75.8% 60.1%
25.3
9.5
9.3
74.7
6.6
89.0%
11a
11b
11c
63.2% 86.1%
37.2% 40.8%
79.2% 194.6b
14.1
5.8
76.9%
36.3%
80.8%
82.0%a 82.6%a
31.6
3.3
24.9
8

11d
11e
11f
62.1% 62.4% 79.8%a 190.7
93.4
22.8
47.4%
82.8%
16.2
74.4% 312.3b
60.9% 293.2b
44.1% 59.6%
43.5% 49.7%
29.1% 69.2%
48.0% 33.3%
60.3% 56.8%
53.8% 88.2%
43.7
12.1
5.9
6.9
1.2
4.3
12a
12b
12c
12d
12e
12f
0.5
14.5
25.6
23.9
91.1
2.9
7.2
36.0
85.9%
73.6%
50.6%
87.4%
67.0%
58.8%
19.6%
15.0
1.8
75.2%a
86.1%a
5.3
6.3
1.1
2.8
1.5
87.4%a
82.3%a
12g
13a
13b
38.6% 75.0% 188.7
17.2
38.0% 25.8% 54.5%a 68.0%a 26.9%a
48.3% 46.5% 290.5
155.0c 23.2c 0.49c
194.8
83.9%a
2.6c
72.2%
18.8c
Cariprazine
/
0.085c
a
Mean inhibitory rates from two independent experiments done in duplicate with 10 μmol/L
concentration.
b Mean Ki values from two independent experiments with eight concentrations in duplicate.
c Data for cariprazine reported by Citrome.20
Initially, we investigated the effects of aryl and alkyl amide moieties. The
affinity profile of compound 9 bearing furan-2-carboxamide moiety at the cyclohexyl
9

side of the molecule was investigated (Table 2). Nanomolar affinities for D2, D3, and
5-HT1ARs (Ki = 19.3 nM, 1.8 nM, and 10.6 nM, respectively), and yet low potential
affinity for 5-HT2AR (87.3%, inhibition ratio) were observed. Moreover, compound
9 had low potential affinity for H1R (82.1%, inhibition ratio) and very weak affinity
for α1R (51.3%, inhibition ratio). Other alkyl amide substituted derivatives (10a-e)
also displayed nanomolar affinities for D2, D3, and 5-HT1ARs, except for 10c (69.9%
inhibition ratio for 5-HT1AR ), but still exhibited moderate to low 5-HT2AR inhibition
ratio (< 90%). The affinities for both α1R and H1R were kept at a low level
(inhibition ratio < 80%). Among these derivatives, compound 9 had both high
affinities for D2, D3, and 5-HT1ARs with low α1R and H1R affinity.
The effect of replacing the amide moiety at the cyclohexyl side of the molecule
with imide moiety was investigated (compounds 11a-f; Table 2). Compounds 11a,
11c and 11e-f with 1,2-cyclohexanedicarboximide, methanoisoindole-1,3(2H)-dione
and tetramethyleneglutarimide substituents showed nanomolar affinities for D2, D3
and 5-HT1A receptors and low potential affinity for α1R (inhibition ratio < 80%).
Nanomolar affinity for the 5-HT2AR was observed for 11f (16.2 nM, Ki). However,
11f showed moderate affinity for the H1R (293.2 nM, Ki), as well as 11c and 11e
(194.6 nM and 312.3 nM, Ki), which was not expected.
The effect of urea moiety at the cyclohexyl side of the molecule was explored
(Table 2, compounds 12a-g). The dimethyl urea 12a showed high affinities for D2,
D3, 5-HT1A and 5-HT2A receptors (Ki < 30 nM, respectively) along with very low
affinities for both α1R and H1R (inhibition ratio < 60%, respectively). Unexpectedly,
other alkyl urea, such as ethyl substituted urea (12b-c) and cyclic urea (12d-e)
exhibited low potential 5-HT2AR affinity (inhabitation ratio < 89%) albeit with
nanomolar receptor affinity for D2 and D3, and low α1R and H1R inhibition (< 70%).
Analogues with aryl substituents (12f-g) also showed nanomolar receptor affinity for
D2 and D3, but the potential affinities for 5-HT1AR and 5-HT2AR were low (inhibition
ratio < 90%). Based on these results, structural modification with methyl urea moiety
(12a) yielded ideal ligand that possessed both high affinity for D2R, D3R, 5-HT1AR,
5-HT2AR and very low affinities for α1R and H1R.
10

Compounds 13a-b (Table 2) were prepared
to investigate the effect of
substitution on the phenyl moiety and chirality of the methyl on the azepine ring.
Compound 13a bearing unsubstituted phenyl ring and racemic methyl on the azepine
ring lost binding affinities for both D2, D3, 5-HT1A, 5-HT2A receptors and α1R and
H1R (inhabitation ratio < 70%). 13b, enantiomer of compound 12a with expected
binding character, had no affinity for α1R and H1R. The D2R and D3R affinities of
13b were decreased to moderate degrees (290.5 nM and 194.8 nM, Ki) as well as low
potential affinity for 5-HT1A/5-HT2A receptors (inhibition ratio < 85%).
Through investigation of substituents in amide moiety, modifications in
substituted 1,2,4,5-tetrahydro-3H-benzo[d]azepine core and preliminary SAR
analysis, the optimal receptor affinity balance was obtained for compound 12a
displaying nanomolar range affinities for the D2, D3, 5-HT1A and 5-HT2A receptors,
and low affinities for α1 and H1 receptors. 12a was selected for further metabolic
stability evaluation in vitro (Table 3) and hERG channel binding assay. The data
indicated that 12a displayed a suitable half-life (t1/2 values were 32.7 min in human
liver microsomes and 23.2 min in rat liver microsomes). 12a was tested in the hERG
functional patch clamp inhibition assay (Qpatch) and micromolar affinity with IC50 =
1.23 μM was observed.
Table 3
Rat and human liver microsomal metabolic stability assay.
Compound
Species
Human
Rat
T1/2 (min)
32.7
CL (μL/min/mg)
42.4
59.7
12a
23.2
Dextromethorphan
Omeprazole
Human
Rat
7.2
36.0
38.5
193.3
Based on in vitro studies, 12a was further characterized in animal models for
behavioral studies. Acute phencyclidine (PCP) can imitate positive symptoms21 and
has been used to simulate schizophrenia symptoms in animals. 12a (1.0, 2.0, and 10.0
mg/kg, p.o.), and classic antipsychotic agent clozapine (10.0 mg/kg, p.o.) and recently
launched cariprazine (0.8 mg/kg, p.o.) produced significant dose-dependent responses
11

in this model compared with PCP-treated group (Fig. 3).
Fig. 3. Inhibition of PCP induced hyperactivity by tested compound and reference
antipsychotic agents clozapine and cariprazine in male Sprague-Dawley rats.
Compounds were administered 20 min before PCP (5 mg/kg) injection. Locomotor
activities were measured for a 1 h duration after PCP administration and the total
travel distance was expressed as Mean ± standard error of the mean (n = 8-10). * and
**, P<0.05 and P<0.01 versus PCP treated group.
In
this
work,
a
series
of
trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine
derivatives were designed and synthesized to identify potential antipsychotics that
target D2/D3/5-HT1A/5-HT2A receptors and have low affinities for α1R and H1R.
Preliminary SAR between the designed compounds and four drug targets, as well as
α1 and H1 receptors was also discussed. The SAR results revealed that the
trans-tetrahydro-3H-benzo[d]azepin-3-yl cyclohexyl amine scaffold was a kind of
privileged structure having low α1 and H1 receptor affinity. The substitutions on the
amine, substitutions at the phenyl and the chirality of the methyl on the azepine ring
had influence on the affinity for the D2, D3, 5-HT1A and 5-HT2A receptors both
individually and collectively. Among these derivatives, compound 12a was confirmed
as an optimal compound. 12a also exhibited suitable metabolic stability and
12

micromolar affinity for hERG channel. Further in vivo animal model tests showed
that 12a was a potential multi-receptor antipsychotic. This study provides insights
into the development of novel multi-target antipsychotic molecule with potential
therapeutic effects and good drug target selectivity.
Acknowledgments
The authors gratefully acknowledge the financial support from the National
Science and Technology Major Project (Grant No. 2019ZX09301116), the National
Natural Science Foundation of China (Grant No. 81803371), Key Technologies R&D
Program of Shanghai Municipal Science and Technology Commission (Grant No.
17431903800), Shanghai Rising-Star Program (Grant No. 19QB1406200). We thank
M.S. Jiao-jiao Chen (College of Pharmaceutical Sciences, Soochow University,
China) for in vivo studies.
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22.
Highlights
•
A series of novel 1,2,4,5-tetrahydro-3H-benzo[d]azepine derivatives have
been synthesized.
•
All compounds were evaluated for D2/D3/5-HT1A/5-HT2A/α1/H1 binding
affinities in vitro.
The optimal compound was screened using the animal model of
locomotor-stimulating effects of phencyclidine.
Compound 12a was a potential multireceptor antipsychotic in animal
behavioral models with good metabolic stability and target selectivity.
23.
14